Skip to main content
SpringerLink
Log in

Failure to Maintain T Cell DNA Methylation and Chromatin Structure Contributes to Human Lupus

  • Chapter
Molecular Autoimmunity

5. Conclusions

The studies summarized in this chapter demonstrate that the failure to maintain DNA methylation patterns in mature CD4+ T cells causes aberrant expression of several methylation-sensitive genes, including LFA-1, perforin, CD70, and likely others, and that their overexpression alters T cell function, promoting autoreactivity, monocyte/macrophage killing, and B cell overstimulation. Furthermore, T cells experimentally demethylated with DNA methyltransferase or ERK signaling pathway inhibitors cause a lupus-like disease in murine models. Procainamide and hydralazine are DNA methylation inhibitors and cause a lupus-like disease in genetically susceptible individuals. Patients with idiopathic lupus have hypomethylated DNA, overexpress the same genes due to the same changes in DNA methylation patterns as in the methylation inhibition model, and demonstrate identical changes in CD4+ T cell function including autoreactive, perforin-mediated monocyte killing and B cell overstimulation. Thus, similar changes in DNA methylation and chromatin structure likely contribute to the pathogenesis of autoimmunity in the DNA hypomethylation model as in idiopathic lupus. The DNA hypomethylation model may also provide an approach to predict additional aberrantly expressed genes in human lupus T cells, since CD11a, perforin, and CD70 were predicted by this model. Finally, these studies also suggest that environmental agents may act by mechanisms analogous to those seen in DIL, triggering changes in chromatin structure and affecting gene expression through signaling inhibition or direct DNA methyltransferase inhibition. Clearly, there is a fundamental role for a failure to maintain DNA methylation patterns and chromatin structure in this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Adams, R.L.P. and Burdon, R.H. (1985). DNA methylation in the cell. In A. Rich (ed.), Molecular Biology of DNA Methylation. Springer-Verlag, New York. pp. 9–18.

    Google Scholar 

  • Amir, R.E., Van den Veyver, I.B., Wan, M., Tran, C.Q., Francke, U., and Zoghbi, H.Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet., 23, 185–188.

    CAS  PubMed  Google Scholar 

  • Antequera, F. and Bird, A. (1993). Number of CpG islands and genes in human and mouse. Proc. Natl. Acad. Sci. U S A, 90, 11995–11999.

    CAS  PubMed  Google Scholar 

  • Attwood, J.T., Yung, R.L., and Richardson, B.C. (2002). DNA methylation and the regulation of gene transcription. Cell. Mol. Life Sci., 59, 241–257.

    CAS  PubMed  Google Scholar 

  • Baylin, S.B. and Herman, J.G. (2000). DNA hypermethylation in tumorigenesis: Epigenetics joins genetics. Trends Genet., 16, 168–174.

    Article  CAS  PubMed  Google Scholar 

  • Bestor, T.H. (1998). The host defence function of genomic methylation patterns. Novartis Foundation Symposium, 214, 187–195; discussion 195–199, 228–232.

    CAS  PubMed  Google Scholar 

  • Chuang, L.S., Ian, H.I., Koh, T.W., Ng, H.H., Xu, G., and Li, B.F. (1997). Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science, 277, 1996–2000.

    Article  CAS  PubMed  Google Scholar 

  • Clark, S.J., Harrison, J., and Molloy, P.L. (1997). Sp1 binding is inhibited by (m)Cp(m)CpG methylation. Gene, 195, 67–171.

    Article  CAS  PubMed  Google Scholar 

  • Comb, M. and Goodman, H.M. (1990). CpG methylation inhibits proenkephalin gene expression and binding of the transcription factor AP-2. Nucleic Acids Res., 18, 3975–3982.

    CAS  PubMed  Google Scholar 

  • Cornacchia, E., Golbus, J., Maybaum, J., Strahler, J., Hanash, S., and Richardson, B. (1988). Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. J. Immunol., 140, 2197–2200.

    CAS  PubMed  Google Scholar 

  • Deng, C., Kaplan, M.J., Yang, J., Ray, D., Zhang, Z., McCune, W.J., Hanash, S.M., and Richardson, B.C. (2001). Decreased Ras-mitogen-activated protein kinase signaling may cause DNA hypomethylation in T lymphocytes from lupus patients. Arthritis Rheum., 44, 397–407.

    Article  CAS  PubMed  Google Scholar 

  • Deng, C., Lu, Q., Zhang, Z., Rao, T., Attwood, J., Yung, R., and Richardson, B. (2003). Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthritis Rheum., 48, 746–756.

    Article  CAS  PubMed  Google Scholar 

  • Deng, C., Yang, J., Scott, J., Hanash, S., and Richardson, B.C. (1998). Role of the Ras-MAPK signaling pathway in the DNA methyltransferase response to DNA hypomethylation. Biol. Chem., 379, 1113–1120.

    CAS  PubMed  Google Scholar 

  • Ehrlich, M. and Wang, R.Y. (1981). 5-Methylcytosine in eukaryotic DNA. Science, 212, 1350–1357.

    CAS  PubMed  Google Scholar 

  • Gladman, D. (2004). Epidemiology of systemic lupus erythematosus. In R.G. Lahita (ed.), Systemic Lupus Erythematosus. Elsevier Academic, New York. pp. 697–715.

    Google Scholar 

  • Glover, A.B. and Leyland-Jones, B. (1987). Biochemistry of azacitidine: A review. Cancer Treatm. Rep., 71, 959–964.

    CAS  Google Scholar 

  • Goldstein, R. and Arnett, F.C. (1987). The genetics of rheumatic disease in man. Rheum. Dis. Clin. N Am., 13, 487–510.

    CAS  Google Scholar 

  • Hansen, R.S., Wijmenga, C., Luo, P., Stanek, A.M., Canfield, T.K., Weemaes, C.M., and Gartler, S.M. (1999). The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc. Natl. Acad. Sci. U S A, 96, 14412–14417.

    CAS  PubMed  Google Scholar 

  • Hess, E.V. (1995). Environmental lupus syndromes. Br. J. Rheum., 34, 597–599.

    CAS  Google Scholar 

  • Holliday, R. and Pugh, J.E. (1975). DNA modification mechanisms and gene activity during development. Science, 187, 226–232.

    CAS  PubMed  Google Scholar 

  • Kammer, G.M., Perl, A., Richardson, B.C., and Tsokos, G.C. (2002). Abnormal T cell signal transduction in systemic lupus erythematosus. Arthritis Rheum., 46, 1139–1154.

    Article  CAS  PubMed  Google Scholar 

  • Kaplan, M.J., Beretta, L., Yung, R.L., and Richardson, B.C. (2000). LFA-1 overexpression and T cell autoreactivity: Mechanisms. Immunol. Invest., 29, 427–442.

    CAS  PubMed  Google Scholar 

  • Kaplan, M.J., Lu, Q., Wu, A., Attwood, J., and Richardson, B. (2004). Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4+ lupus T cells. J. Immunol., 172, 3652–3661.

    CAS  PubMed  Google Scholar 

  • Kobata, T., Jacquot, S., Kozlowski, S., Agematsu, K., Schlossman, S.F., and Morimoto, C. (1995). CD27-CD70 interactions regulate B-cell activation by T cells. Proc. Natl. Acad. Sci. U S A, 92, 11249–11253.

    CAS  PubMed  Google Scholar 

  • Kyttaris, V. and Tsokos, G. (2003). Uncovering the genetics of systemic lupus erythematosus: Implications for therapy. Am. J. Pharmacogenomics, 3, 193–202.

    Article  CAS  PubMed  Google Scholar 

  • Lens, S.M., Tesselaar, K., van Oers, M.H., and van Lier, R.A. (1998). Control of lymphocyte function through CD27-CD70 interactions. Semin. Immunol., 10, 491–499.

    Article  CAS  PubMed  Google Scholar 

  • Li, E., Bestor, T.H., and Jaenisch, R. (1992). Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell, 69, 915–926.

    CAS  PubMed  Google Scholar 

  • Liossis, S. and Tsokos, G. (1999). B cells in systemic lupus erythematosus. In G. Kammer and G. Tsokos (eds), Lupus. Molecular and Cellular Pathogenesis. Humana Press Inc, Totowa, New Jersey. pp. 167–180.

    Google Scholar 

  • Lu, Q., Kaplan, M., Ray, D., Ray, D., Zacharek, S., Gutsch, D., and Richardson, B. (2002). Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus. Arthritis Rheum., 46, 1282–1291.

    Article  CAS  PubMed  Google Scholar 

  • Lu, Q., Wu, A., Ray, D., Deng, C., Attwood, J., Hanash, S., Pipkin, M., Lichtenheld, M., and Richardson, B. (2003). DNA methylation and chromatin structure regulate T cell perforin gene expression. J. Immunol., 170, 5124–5132.

    CAS  PubMed  Google Scholar 

  • Mevorach, D., Zhou, J.L., Song, X., and Elkon, K.B. (1998). Systemic exposure to irradiated apoptotic cells induces autoantibody production. J. Exp. Med., 188, 387–392.

    CAS  PubMed  Google Scholar 

  • Mongey, A.-B. and Hess, E.V. (2002). The role of environment in systemic lupus erythematosus and associated disorders. In D.J. Wallace and B.H. Hahn (eds), Dubois’s Lupus Erythematosus. Lippincott Williams and Wilkins, Philadelphia. pp. 33–64.

    Google Scholar 

  • Oelke, K., Lu, Q., Richardson, D., Wu, A., Deng, C., Hanash, S., and Richardson, B. (2004). Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors. Arthritis Rheum., 50, 1850–1860.

    Article  CAS  PubMed  Google Scholar 

  • Okano, M., Bell, D.W., Haber, D.A., and Li, E. (1999). DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell, 99, 247–257.

    Article  CAS  PubMed  Google Scholar 

  • Okano, M., Xie, S., and Li, E. (1998a). Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. Nucleic Acids Res., 26, 2536–2540.

    Article  CAS  PubMed  Google Scholar 

  • Okano, M., Xie, S., and Li, E. (1998b). Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat. Genet., 19, 219–220.

    CAS  PubMed  Google Scholar 

  • Quddus, J., Johnson, K.J., Gavalchin, J., Amento, E.P., Chrisp, C.E., Yung, R.L., and Richardson, B.C. (1993). Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. J. Clin. Invest., 92, 38–53.

    CAS  PubMed  Google Scholar 

  • Richardson, B. (1986). Effect of an inhibitor of DNA methylation on T cells. II. 5-Azacytidine induces self-reactivity in antigen-specific T4+ cells. Hum. Immunol., 17, 456–470.

    Article  CAS  PubMed  Google Scholar 

  • Richardson, B., Kahn, L., Lovett, E.J., and Hudson, J. (1986). Effect of an inhibitor of DNA methylation on T cells. I. 5-Azacytidine induces T4 expression on T8+ T cells. J. Immunol., 137, 35–39.

    CAS  PubMed  Google Scholar 

  • Richardson, B., Powers, D., Hooper, F., Yung, R.L., and O’Rourke, K. (1994). Lymphocyte function-associated antigen 1 overexpression and T cell autoreactivity. Arthritis Rheum., 37, 1363–1372.

    CAS  PubMed  Google Scholar 

  • Richardson, B., Scheinbart, L., Strahler, J., Gross, L., Hanash, S., and Johnson, M. (1990). Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum., 33, 1665–1673.

    CAS  PubMed  Google Scholar 

  • Richardson, B.C., Buckmaster, T., Keren, D.F., and Johnson, K.J. (1993). Evidence that macrophages are programmed to die after activating autologous, cloned, antigen-specific, CD4+ T cells. E. J. Immunol., 23, 1450–1455.

    CAS  Google Scholar 

  • Richardson, B.C., Liebling, M.R., and Hudson, J.L. (1990). CD4+ cells treated with DNA methylation inhibitors induce autologous B cell differentiation. Clin. Immunol. Immunopathol., 55, 368–381.

    Article  CAS  PubMed  Google Scholar 

  • Richardson, B.C., Strahler, J.R., Pivirotto, T.S., Quddus, J., Bayliss, G.E., Gross, L.A., O’Rourke, K.S., Powers, D., Hanash, S.M., and Johnson, M.A. (1992). Phenotypic and functional similarities between 5-azacytidine-treated T cells and a T cell subset in patients with active systemic lupus erythematosus. Arthritis Rheum., 35, 647–662.

    CAS  PubMed  Google Scholar 

  • Riggs, A.D. (1985). X-inactivation, DNA methylation, and differentiation revered. In A. Razin, H. Cedar, and A.D. Riggs (eds), DNA Methylation: Biochemistry and Biological Significance. Springer-Verlag, New York. pp. 269–278.

    Google Scholar 

  • Scheinbart, L.S., Johnson, M.A., Gross, L.A., Edelstein, S.R., and Richardson, B.C. (1991). Procainamide inhibits DNA methyltransferase in a human T cell line. J. Rheumatol., 18, 530–534.

    CAS  PubMed  Google Scholar 

  • Stoger, R., Kubicka, P., Liu, C.G., Kafri, T., Razin, A., Cedar, H., and Barlow, D.P. (1993). Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell, 73, 61–71.

    Article  CAS  PubMed  Google Scholar 

  • Tsao, B.P. and Grossman, J.M. (2001). Genetics and systemic lupus erythematosus. Curr. Rheumatol. Rep., 3, 183–190.

    CAS  PubMed  Google Scholar 

  • Walport, M.J. (2000). Lupus, DNase and defective disposal of cellular debris. Nat. Genet., 25, 135–136.

    Article  CAS  PubMed  Google Scholar 

  • Yoder, J.A., Soman, N.S., Verdine, G.L., and Bestor, T.H. (1997). DNA (cytosine-5)-methyltrans-ferases in mouse cells and tissues. Studies with a mechanism-based probe. J. Mol. Biol., 270, 385–395.

    Article  CAS  PubMed  Google Scholar 

  • Yu, F., Thiesen, J., and Stratling, W.H. (2000). Histone deacetylase-independent transcriptional repression by methyl-CpG-binding protein 2. Nucleic Acids Res., 28, 2201–2206.

    CAS  PubMed  Google Scholar 

  • Yung, R., Chang, S., Hemati, N., Johnson, K., and Richardson, B. (1997). Mechanisms of drug-induced lupus. IV. Comparison of procainamide and hydralazine with analogs in vitro and in vivo. Arthritis Rheum., 40, 1436–1443.

    CAS  PubMed  Google Scholar 

  • Yung, R., Kaplan, M., Ray, D., Schneider, K., Mo, R.R., Johnson, K., and Richardson, B. (2001). Autoreactive murine Th1 and Th2 cells kill syngeneic macrophages and induce autoantibodies. Lupus, 10, 539–546.

    Article  CAS  PubMed  Google Scholar 

  • Yung, R., Powers, D., Johnson, K., Amento, E., Carr, D., Laing, T., Yang, J., Chang, S., Hemati, N., and Richardson, B. (1996). Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice. J. Clin. Invest., 97, 2866–2871.

    CAS  PubMed  Google Scholar 

  • Yung, R.L., Quddus, J., Chrisp, C.E., Johnson, K.J., and Richardson, B.C. (1995). Mechanism of druginduced lupus. I. Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo. J. Immunol., 154, 3025–3035.

    CAS  PubMed  Google Scholar 

  • Yung, R.L. and Richardson, B.C. (1994). Drug-induced lupus. Rheum. Dis. Clin. N. Am., 20, 61–86.

    CAS  Google Scholar 

  • Yung, R.L. and Richardson, B.C. (2003). Drug-induced lupus. In M. Hochberg, A. Silman, J. Smolen, M. Weinblatt, and M. Weisman (eds) Rheumatology. Harcourt Health Sciences, London.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, University of Michigan, Michigan, 48109-0940

    Donna Ray & Bruce Richardson

Authors
  1. Donna Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruce Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institut National de Santé et de Recherche Médicale (INSERM), Paris, France

    Moncef Zouali

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Springer Science+Business Media, Inc.

About this chapter

Cite this chapter

Ray, D., Richardson, B. (2005). Failure to Maintain T Cell DNA Methylation and Chromatin Structure Contributes to Human Lupus. In: Zouali, M. (eds) Molecular Autoimmunity. Springer, Boston, MA. https://doi.org/10.1007/0-387-24534-0_6

Download citation

Publish with us

Policies and ethics

Search

Navigation